The serotonin transporter is a potential susceptibility factor for bipolar affective disorder

Collier, David; Arranz, Maria; Sham, Pak C.; Battersby, S.; Vallada, Homero; Gill, Paul; Aitchison, Katherine; Sodhi, Monsheel S.; Li, Tao; Roberts, Gareth W.; Smith, B. V.; Morton, John C.; Murray, Robin M.; Smith, Dale L.; Kirov, George

doi:10.1097/00001756-199607080-00030

Cited by 188 publications

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“…In total, 17 population-based studies 9,14,33,34,38,46,50,51,56,60,61,66,[68][69][70] and six family-based studies 12,32,42,53,63,74 were about 5-HTTLPR. A total of 16 population-based studies 27,33,35,38,41,47,[49][50][51]54,56,58,60,61,70,75 and four family-based studies 12,52,57,63 were about the intron 2 VNTR. Among the population-based studies, some used matched controls according to the ethnicity 41,47,50,60,66,69 and others explicitly verified the ethnic homogeneity of the sample through the ancestry history.…”

Section: Resultsmentioning

confidence: 99%

“…51 The remaining studies mentioned that the sample was ethnically homogeneous. 9,14,34,35,49,54,58,61,68,70,75 5-HTTLPR meta-analysis In total, 17 population-based studies comprised 1712 cases (ie 3424 alleles) and 2583 controls, whereas six family-based studies comprised 587 trios. Summaries are shown in the Tables 1 and 2.…”

Section: Resultsmentioning

confidence: 99%

“…According to the forest plot of the 5-HTTLPR, Mynett-Johnson et al (2000), 12 Hauser et al (2003) 34 and Rotondo et al (2002) 9 stood apart as an apparent cluster. The forest plot of the intron 2 VNTR showed Kunugi et al, 38 Heiden et al (2000) 35 and Collier et al (1996b) 58 as an apparent cluster. However, we could not identify any particular characteristics shared by these studies that might cause them to stand apart.…”

Section: Discussionmentioning

confidence: 98%

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Population-based and family-based studies on the serotonin transporter gene polymorphisms and bipolar disorder: a systematic review and meta-analysis

et al. 2005

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The serotonin transporter (5-HTT) is a candidate gene for bipolar disorder (BPD). It has been investigated for association with the illness in a series of studies, but overall results have been inconsistent and its role in the disorder remains controversial. Systematic reviews using metaanalytical techniques are a useful method for objectively and reproducibly assessing individual studies and generating combined results. We performed two meta-analyses of published studies-both population-based and family-based studies-investigating the association between BPD and the 5-HTT gene-linked polymorphic region (5-HTTLPR) and the intron 2 variable numbers of tandem repeats (VNTR) polymorphisms. The literature was searched using Medline and Embase to identify studies for inclusion. We statistically joined population-based and family-based studies into a single meta-analysis. For both polymorphisms, our review revealed significant pooled odds ratios (ORs): 1.12 (95% CI 1.03-1.21) for the 5-HTTLPR and 1.12 (95% CI 1.02-1.22) for the intron 2 VNTR. Meta-regression showed that neither the study type (population-based vs family-based; P ¼ 0.41 for the 5-HTTLPR and P ¼ 0.91 for the intron 2 VNTR) nor the sample ethnicity (Caucasian vs non-Caucasian; P ¼ 0.35 for the 5-HTTLPR and P ¼ 0.66 for the intron 2 VNTR) significantly contributed to the heterogeneity of the meta-analyses. The observed ORs could be regarded simply as a very small but detectable effect of the 5-HTT, which has an additive effect when combined with other susceptibility loci. Alternative hypotheses on this finding were also discussed: a stronger effect of the haplotypes involving the two polymorphisms or other SNP markers; a more direct effect of these polymorphisms on specific phenotypes of BPD; and the presence of gene-environment interaction as a mediator of the genetic effects of 5-HTT. Keywords: bipolar disorder; serotonin transporter; polymorphisms; genetics; association study; meta-analysis Bipolar disorder (BPD), also known as manic-depressive illness, is a frequent and severe psychiatric disorder with the lifetime prevalence between 1 and 2% in the general population, being equally distributed across sexes. 1 The etiology is unknown although the presence of a complex dysfunction at multiple levels such as neurotransmitter system, prefrontallimbic-subcortical circuit and neuroendocrinological system has been suggested. 2 Family studies have indicated a marked increase in lifetime risk of the illness in first-degree relatives of the proband, varying between five and 10 times that of the general population. 3 Twin studies have shown an increased risk in monozygotic co-twins compared with dizygotic co-twins of a proband with BPD. The risk in monozygotic co-twins has been estimated at 45-75 times that of the general population. 3,4 Adoption studies have also shown that the risk of BPD is greater in biological relatives than in adoptive relatives of the probands. 5 Most of the segregation studies have shown that the inheritance of BPD cannot be explained b...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 98%

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Population-based and family-based studies on the serotonin transporter gene polymorphisms and bipolar disorder: a systematic review and meta-analysis

et al. 2005

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“…In keeping with: (i) the compelling and extensive evidence for central 5-hydroxytryptamine (5-HT, serotonin) playing a role in mood disorders; and (ii) the key role of the 5-HT transporter, which, by allowing high-affinity reuptake of 5-HT into serotonergic neurones, regulates 5-HT neurotransmission (Amara and Kuhar 1993), the findings that allelic variations in (Collier et al 1996a;Ogilvie et al 1996) or nearby (i.e., promoter region) (Lesch et al 1996;Collier et al 1996b) the 5-HT transporter gene may have weaken, but significant impacts on affective and anxiety disorders are unsurprising. Moreover, because polymorphism of disease-related genes may also be predictive of drug response (Kleyn and Vesell 1998), it is then not a surprise that the polymorphism within the promoter region of the 5-HT transporter gene leads to a genetic variability of the antidepressant response to the selective serotonin reuptake inhibitor (SSRI) fluvoxamine (Smeraldi et al 1998).…”

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confidence: 93%

Serotonin Reuptake Inhibition by Citalopram in Rat Strains Differing for Their Emotionality

Pollier

Sarre

Aguerre

et al. 2000

Neuropsychopharmacology

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“…The gene coding for it has been proposed as a possible candidate for involvement in the pathogenesis of major psychoses. A functional polymorphism in the upstream regulatory region of the gene has been associated with both major depressive and bipolar disorders, [43][44][45] although subsequent studies did not replicate these results. [46][47][48][49][50][51][52][53][54][55][56][57][58] The polymorphism in the upstream is a deletion/insertion (SERTPR) located exactly at the 5 0 -flanking regulatory region of serotonin transporter gene on chromosome 17q11.2.…”

Section: Introductionmentioning

confidence: 99%

Further evidence for a possible association between serotonin transporter gene and lithium prophylaxis in mood disorders

et al. 2004

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We previously reported an association between the functional polymorphism in the upstream regulatory region of the serotonin transporter gene (SERTPR) and the prophylactic efficacy of lithium in a sample of 201 Italian subjects affected by Mood disorders. The aim of the present study was to replicate analyses on an independent sample. In total, 83 subjects affected by Bipolar disorder were recruited in the Mood Disorders Clinic of the Eginition Hospital of the Athens University, Medical School Department of Psychiatry. All patients were administered with lithium as prophylactic therapy and they were prospectively observed for at least 3 years. Subjects were typed for their SERTPR variant using polymerase chain reaction techniques. SERTPR variants were associated with lithium outcome among those subjects who had few manic episodes before lithium treatment and, as a trend, among subjects who received a high daily dose of lithium (X1200 mg/die). In both cases, subjects with the l/l variant showed a higher probability to develop an illness episode within 3 years of prophylactic treatment with lithium. The present study confirmed our previous observation of a better response of SERTPR*l/s carriers, but could not confirm a poor efficacy in subjects with the SERTPR*s/s genotype. Notwithstanding the conflicting results, SERTPR variants are a possible liability factor for lithium long-term efficacy in mood disorders. Further studies on independent and large samples are required to determine the reliability and direction of the possible association between SERTPR variants and lithium outcome. INTRODUCTIONLithium is an effective prophylactic agent in mood disorders but not all patients equally respond to lithium therapy. Clinical predictors account for less than half of the variance, 1-8 and there are evidences suggesting that genetic factors play a substantial role in lithium prophylaxis effectiveness. [9][10][11][12][13][14][15][16][17][18][19][20] A large number of studies reported an association between prophylactic lithium response and a family history of bipolar disorder, 10,[12][13][14]17 although not unequivocally confirmed. [21][22][23][24][25] Recently, Grof et al 26 reported that lithium response in a sample of relatives of responder probands was 67% compared to 30% in the comparison group.

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The serotonin transporter is a potential susceptibility factor for bipolar affective disorder

Cited by 188 publications

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Population-based and family-based studies on the serotonin transporter gene polymorphisms and bipolar disorder: a systematic review and meta-analysis

Population-based and family-based studies on the serotonin transporter gene polymorphisms and bipolar disorder: a systematic review and meta-analysis

Serotonin Reuptake Inhibition by Citalopram in Rat Strains Differing for Their Emotionality

Further evidence for a possible association between serotonin transporter gene and lithium prophylaxis in mood disorders

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